Project Summary/Abstract ? Project 1 Previous animal-based experiments in this Project focused on the impact of vascular capacitance (blood storage) on cardiovascular regulation. Because the splanchnic vasculature plays a large role in determining overall vascular capacitance, and the sympathetic nervous system is the major regulator of splanchnic vascular capacitance, we investigated the idea that the splanchnic sympathetic nerves may be important in hypertension. Obesity is now known to be the major cause of human hypertension and its accompanying morbidities, mortalities and increased health care costs. Furthermore, increased sympathetic nervous system activity is accepted as one critical link between obesity and hypertension. Although sympathetic control of the kidney is an established factor in obesity-related hypertension, there is substantial evidence that sympathetic activity to other targets also plays a part. Given the close association of obesity-related sympathetic overactivity and hypertension with accumulation of inflammed adipose tissue specifically in the splanchnic region (visceral adipose tissue), we hypothesize that splanchnic sympathetic activity is important in obesity- associated hypertension. We further propose that splanchnic sympathetic activity regulates arterial pressure in obesity not only by affecting the function of splanchnic blood vessels, but also by promoting and accelerating inflammation of the visceral adipose tissue surrounding those blood vessels. In this context, splanchnic sympathetic activity refers not only to effects of sympathetic nerves and circulating catecholamines, but also to norepinephrine released from a newly discovered adrenergic system intrinsic to visceral fat itself (described in Project 3).To test these hypotheses, experiments will be conducted in rats made obese by feeding them a high fat (HF) diet for up to 26 weeks, starting at 3 weeks of age. The rats will develop glucose intolerance, visceral obesity and hypertension starting between 12-18 weeks of the diet. At 6, 18 and 26 weeks of HF feeding we will estimate splanchnic nerve activity using norepinephrine spillover; measure vascular capacitance (mainly splanchnic), splanchnic vascular resistance and their dependence on adrenergic input; and evaluate the impact of chronic denervation of splanchnic blood vessels and visceral adipose tissue on hypertension development. Finally, we will determine if prostaglandin D2 in the brain contributes to sympathoexcitation in our rat model of obesity. It is anticipated that these studies could produce new approaches to managing obesity-related hypertension.